Community-associated methicillin-resistant Staphylococcus aureus (CA-MRSA) causes skin and soft tissue infections (SSTI) in military recruits. CA-MRSA colonization is a risk factor for the development of SSTI. We evaluated whether 2% chlorhexidine-impregnated (CHG) cloths reduce SSTI rates and skin colonization with S. aureus during recruit training. In 2007 we enrolled recruits over 4 training periods. Platoons were cluster randomized to receive CHG cloths or control cloths applied over the entire body 3 times weekly. Subjects were monitored daily for SSTI. Serial nasal and axillary swabs were collected at in-processing and every 2 weeks thereafter to assess S. aureus colonization. Of 1562 subjects enrolled, 781 (23 platoons) received CHG and 781 (21 platoons) received control treatment. Compliance (use of >=50% of wipes) was equal between groups (50-60%) and gradually declined over the 6-week period. Rates of S. aureus colonization were similar for both the CHG group and control group at baseline: axilla 11%, nares 42%, and either site 45%. The incidence of colonization increased in both groups; however, the rates were lower in the CHG group vs. the control group (axilla: 26 vs 34%; nares: 47% vs. 62%; either site: 56% vs. 69%). The SSTI 6-week rate in the CHG group was 9.4% vs. 7.1% in the control group (P=0.13). In conclusion, CHG applied 3 times a week did not reduce rates of SSTI in recruits. S. aureus colonization increased over time in all platoons but to a lesser extent in those assigned CHG. SSTI control strategies other than decolonization and transmission dynamics of S. aureus colonization in recruits requires additional investigation. Additionally, studies are now underway to (1) determine the frequency of strains resistant to methicillin (oxacillin), clindamycin, erythromycin, trimethoprim-sulfamethoxazole, or ciprofloxacin; and (2) determine if a virulent strain of S. aureus or a heterogeneous collection of strains is the predominant cause of SSTIs.